1. Field of the Invention
This invention relates to film-forming compositions of anti-hyperalgesic opiates having substantially no effects on the central nervous system and method of topically treating hyperalgesic conditions.
The present invention also relates to compositions and methods for the prevention and/or treatment of itch, also known as prutitus, which has many causes. The compositions which are formulated for topical administration contain antihyperalgesic opiates that are substantially devoid of central nervous system effects, and, thus, have very little, if any potential for producing side effects with centrally acting antihyperalgesic opiates.
2. Reported Developments
A) Antihyperalgesic Opiates
Pain is the effect of noxious stimuli on nerve endings of a subject which results in the transmission of impulses to the cerebrum. This sensation informs the subject of actual or impending tissue damage and elicits a defensive response. The degree of response substantially correlates with the degree of noxious stimuli in order to speedily avoid further tissue damage and to re-establish normal pre-injury conditions in the subject. The sensation of pain, however, does not end with the stoppage of the noxious stimuli but continues to persist during the inflammation stage of the injury. In turn, the continuation of pain perception causes discomfort to, and deleterously affects the well-being of, the subject. It is, therefore, important to reduce and/or eliminate pain perception of a subject subsequent to injuries.
The reduction/elimination of pain perception can be affected by the central nervous system (hereinafter sometimes referred to as CNS)-mediated analgesia which leads to an overall inhibition of the pain transmission. CNS-mediated analgesia can be effected by systemically administered opiates which, by interaction with specific receptors in the brain and spinal cord, are able to block pain transmission. Systemic opiates, such as morphine, which have been used for many years to control post injury pain, have side effects because their actions within the brain include sedation, depression of respiration, constipation, nausea and development of addiction and dependence. When peripherally applied, opiates have a short duration of action and still possess the undesirable side effects.
Certain opiates, such as loperamide i.e., 4-(p-chlorophenyl)-4-hydroxy-N-N-dimethyl-.alpha.,.alpha.-diphenyl-1-piper idinebutyramide hydrochloride! and its analogs were reported to be devoid of CNS effects, which is believed to be due to the failure of the opiates to cross the blood brain barrier. Loperamide HCl has been used for a long time in antidiarrheal formulations and has been completely free of the undesirable CNS effects. It would be desirable to use such opiates to inhibit/eliminate post-injury pain without concomitant CNS effects.
The present invention provides safe and effective topical film-forming compositions for inhibiting/eliminating the sensation of pain.
B) Antihyperalgesic Opiates as Anti-Pruritic Agents
The prior art has investigated the physiology and treatment of prutitus as illustrated hereunder.
Itch is a well known sensory state associated with the desire to scratch. As with pain, itch can be produced by a variety of chemical, mechanical, thermal or electrical stimuli. In addition to the difference in the sensory quality of itch and pain, they also differ in that (1) itch, unlike pain, can only be evoked from the superficial layers of skin, mucosa, and conjunctiva, and (2) itch and pain usually do not occur simultaneously from the same skin region; in fact, mildly painful stimuli, such as scratching, are effective in eliminating itch. In addition, the application of histamine to skin produces itch but not pain. Itch and pain are further dissociated pharmacologically: itch appears to be insensitive to opiate and non-steroidal anti-inflammatory drug (NSAID) treatment, both of which are effective in treating pain.
Although itch and pain are of a class in that both are modalities of nociception transmitted by small unmyelinated C fibers, evidence that itch is not just a variety of low-threshold pain is overwhelming. Itch leads to the reflex or urge to scratch; pain leads to withdrawal Removal of the epidermis eliminates itch but causes pain. Analgesics, particularly opiods, relieve pain but often cause itch (see, for example J. Am. Acad. Derm. 24: 309-310, 1991). There can be no doubt that itching is of eminent clinical importance; many systemic and skin diseases are accompanied by persistent or recurrent itch attacks. Current knowledge suggests that itch has several features in common with pain but exhibits intriguing differences as well (see, for example, W. Magerl, IASP Newsletter, pp. 4-7, Sept/Oct 1996).
McMahon et al (TINS, Vol. 15, No. 12, pp. 497-501, 1992) provides a description of stimuli (Table a) and a comparison of the established features of itch and pain (Table b):
TABLE a ______________________________________ Stimuli that can elicit or augment itch ______________________________________ Physical Mechanical. Light touch, pressure, suction. Thermal. Warming. Electrical. Focal transcutaneous repetitive stimulation, transcutaneous constant current stimulation, intraneural microstimulation. Chemical Non-specific irritants. Acids, alkalis. Inflammatory mediators. Histamine, kallikrein, bradykinin, prostaglandins. Histamine-releasing substances. Compound 48/80, protamine, C3a. Peptidases. Mucunain, papain, trypsin, mast cell chymase. Neuropeptides. Substance P, vasoactive intestinal polypeptide, neurotensin, secretin. Opioids. Morphine, .beta.-endorphin, enkephalin analogues. ______________________________________
TABLE b ______________________________________ Comparison of the established features of itch and pain ITCH PAIN ______________________________________ Psychophysiology Tissue Skin. Mucous membranes Most tissues Stimulus See Table a Many stimuli Intraneural micro- Occasionally Yes stimulation Secondary sensations Alloknesis (itchy skin) Hyperalgesia Psychogenic modifica- Pronounced Present tion Counterstimuli Scratching, pain, cooling Tactile stimuli, cooling Neurophysiology Primary afferent C- and A.delta.-fibres C- and A.delta.-fibres neurones Flare size Large Small Spinal pathway Anterolateral funiculus Anterolateral funiculus Protective reflexes Scratching, sneezing Flexion, guarding Autonomic reflexes Yes Yes Pharmacology Capsaicin sensitivity Yes Chemogenic pain; yes NSAID sensitivity Probably not Yes Morphine sensitivity No Yes ______________________________________ Abbreviation: NSAID, nonsteroidal antiinflammatory drugs.
Experimental focal itch stimuli are surrounded by a halo of seemingly unaffected tissue where light tactile stimuli are capable of eliciting itch-like sensations. The term itchy skin or alloknesis has been coined for these secondary sensations that are reminiscent of the features of secondary hyperalgesia evolving around a painful focus. A crucial observation is that itch and pain usually do not coexist in the same skin region and a mild noxious stimulus such as scratching is in fact the singly most effective way to abolish itch. This abolition of itch can be prolonged producing an `antipruritic state`. Although mild scratch is often not painful, microneurographic recordings from humans have directly determined that such stimuli are among the most effective ways to excite cutaneous unmyelinated nociceptive afferents. (See, for example:
Shelly, W. B. and Arthur, R. P. (1957) Arch. Dernatol. 76, 296-323; PA1 Simone, D. A. et al. (1987) Somatosens. Res. 5, 81-92; PA1 Graham, D. T. , Goodell, H. and Wolff, H. G. (1951) J. Clin. Invest. 30, 37-49; PA1 Simone, D. A., Alreja, M. and LaMotte, R. H. (1991) Somatosens, Mot. Res. 8, 271-279; PA1 Torebjork, E (1985) Philos. Trans. R. Soc. London Ser. B 308, 227-234; and PA1 Vallbo, A. B., Hagbarth, K. E., Torebjork, H. E. and Wallin, B. G. (1979) Physiol. Rev. 59,919-957). PA1 (a) from about 1.0 to about 65% w/w of an anti-hyperalgesic/anti-pruritic compound incorporated in a film-forming polymeric material; PA1 (b) said film-forming polymeric material being present in said composition of from about 1 to about 76% w/w and is capable of forming an essentially continuous film in the pH environment of from about 5.5 to about 8.5, said polymeric material having atoms containing polarizable electrons thereon, said atoms being selected from the group consisting of oxygen, nitrogen, sulfur in combination with a divalent cation, said divalent cation is selected from the group consisting of Ca.sup.++, Mg.sup.++, Zn.sup.++ and Ba.sup.++ wherein the ratio of said atoms containing polarizable electrons thereon to said divalent cations is in the range of from about 7.7 to about 1; and PA1 (c) of from about 23 to about 34% w/w of an aqueous pharmaceutically acceptable carrier. PA1 (a) Loperamide, its analogs, and its related compounds, metabolites and prodrugs thereof reported in U.S. Pat. Nos. PA1 (i) each is independently selected from aryl and heteroaryl groups containing from 5 to 7 members in the ring, each is unsubstituted or substituted with one or more substituents selected from halo, haloalkyl, hydroxy, alkyl, alkyloxy, aminosulfonyl, alkylcarbonyl, nitro, haloalkyl, trifluoromethyl, amino, aminocarbonyl, phenylcarbonyl or thienyl, where the alkyl groups are straight or branched chains lower alkyl containing from 1 to 6 carbon atoms; or PA1 (ii) Ar.sup.1 and Ar.sup.2 are each independently phenyl or pyridyl groups and with the carbon to which they are commonly linked form a fused ring so that the compounds of formula (1) have the structure: ##STR4## wherein n is 0 to 3; R.sup.2 is either alkyl in which the alkyl group is a straight or branched chain having 1 to 12 carbon atoms, or is alkylene having 1 to 6 carbon atoms with one or two double bonds; PA1 R.sup.3 is Ar.sup.3, --Y--Ar.sup.3, where Y is alkylene or alkyl having 1 to 3 carbon atoms, or is ##STR5## R.sup.8 is hydrogen or alkyl that is a straight or branched chain containing from 1 to 6 carbon atoms; PA1 Ar.sup.3 is aryl or heteroaryl containing from 5 to 7 members in the ring, which is unsubstituted or substituted with one or more substituents of halo, halo lower alkyl or lower alkyl; PA1 Ar.sup.4 is either: PA1 R is hydrogen, alkyl, halo, haloalkyl or OR.sup.9 ; PA1 R.sup.9 is selected from alkyl arylalkyl, alkylcarbonyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl in which the alkyl groups are straight or branched chains containing 1 to 12 carbon atoms; PA1 R.sup.4 is selected from among: PA1 R.sup.7 is selected from among: PA1 R.sup.16 is hydrogen or lower alkyl; PA1 A. sulfated polysaccharides; PA1 B. carboxylated polysaccharides; PA1 C. cellulose derivatives; and PA1 D. sulfated, sulfonated or carboxylated synthetic polymers. PA1 R=CH.sub.3 ; C.sub.2 H.sub.5 ; C.sub.3 H.sub.7 ; PA1 R"=CH.sub.3 ; C.sub.2 H.sub.5 ; and PA1 M.sup.++ =Ca.sup.++, Zn.sup.++, Ba.sup.++, or Mg.sup.++. PA1 Sodium ethylcellulose sulfate; PA1 Sodium cellulose acetate sulfate; and PA1 Sodium carboxymethyl cellulose. PA1 A. Polysaccharides PA1 B. Cellulose Derivatives PA1 C. Synthetic Polymers PA1 (a) of from about 1.0 to about 65% w/w of an anti-hyperalgesic/anti-pruritic compound; PA1 (b) of from about 1 to about 76% w/w of a polymeric material having atoms containing polarizable electrons thereon in combination with a divalent cation in a ratio of from about 7.7 parts to about 1 part or less; and PA1 (c) from about 23 to about 34% w/w of a pharmaceutically acceptable carrier.
Physiologically, there is evidence that substance P released from nociceptor terminals can cause the release of histamine from mast cells. Activation of mast cells, with release of the pruritogen histamine, occurs in immediate type hypersensitivity diseases, such as anaphylactic reactions and urticaria. Urticarial eruptions are distinctly pruritic and can involve any portion of the body, and have a variety of causes beyond hypersensitivity, including physical stimuli such as cold, solar radiation, exercise and mechanical irritation. Other causes of prutitus include: chiggers, the larval form of which secretes substance that creates a red papule that itches intensely; secondary hyperparathyroidism associated with chronic renal failure; cutaneous larva migrans, caused by burrowing larvae of animal hookworms; dermal myiasis, caused by maggots of the horse botfly, which can afflict horseback riders; onchocerciasis ("river blindness") caused by filarial nematodes; pediculosis, caused by lice infestations; enterobiasis (pinworm) infestations, which afflict about 40 million Americans, particularly school children; schistosome dermatitis (swimmer's itch); psoriasis; poison ivy; and asteatotic eczema ("winter itch"). The role of histamine or other endogenous pruritogens in mediating itch associated with these and other pruritic conditions, such as atopic dermatitis, its not yet well established. For atopic dermatitis, in particular, it appears that itch is not inhibited by antihistamines, but by cyclosporin A, a drug which inhibits the production of cytokines which have been proposed as potential pruritogens.
Current therapies for the treatment of itch include a variety of topical and systemic agents, such as steroids, antihistamines, and some psychotherapeutic tricyclic compounds, such as doxepin hydrochloride. Many such agents are listed in PDR Generics (see Second Edition, 1996, p. cv for a listing of said agents). The limitations of these agents are well known to medical practitioners, and are summarized in the "Warnings" and "Precautions" sections for the individual agents listed in PDR Generics. In particular, the lack of complete efficacy of antihistamines is well known, but antihistamines are frequently used in dermatology to treat prutitus due to urticaria, atopic dermatitis, contact dermatitis, psoriasis, and a variety of other conditions. Although sedation has been a frequent side effect of conventional systemically administered antihistamines, a new generation of antihistamines have been developed that are nonsedating, apparently due to their inability to cross the blood-brain barrier.
Intravenous administration of opiate analgesics, such as morphine and hydromorphone has been associated with prutitus, urticaria, other skin rashes, and wheal and flare over the vein being injected. These itch and itch-related reactions are believed to be due to a histamine-releasing property of these opiates, via mast cell degranulation. These opiates are thought to act upon the mu subtype of opiate receptor, but the possibility of interactions at the other principal opiate receptor subtypes (delta and kappa) cannot be excluded since these and other pruritogenic analgesics are not pure mu agonists. The cellular loci of the receptor type(s) mediating the itching effect is not known, although the mast cell is a possible candidate since opiates cause histamine release from these cells. However, some investigators have suggested that the frequent inability of antihistamines to block morphine-induced itching suggests a non-histaminergic mediation of opiate-induced itching--mechanism which could involve central opiate receptors. Although i.v. morphine only occasionally results in general itching (in about 1% of patients), prutitus is more prevalent in opiate analgesia with epidural (8.5%) or intraspinal (45.8%) administration. (See, for example: Bernstein et al., "Antipruritic Effect of an Opiate Antagonist, Naloxone Hydrochloride", The Journal of Investigative Dermatology, 78:82-83, 1982; and Ballantyne et al., "Itching after epidural and spinal opiates", Pain, 33: 149-160, 1988.)
To date, treatment with opiates has not only proven useless in the treatment of itch, but appears to exacerbate itch in mammals. The consistent findings from human studies indicate that whether by central or peripheral mechanisms, opiates appear to promote rather than prevent itching, and that opiate antagonists have antipuritic activity.
Human clinical studies have generally shown that opiates cause itching and there is evidence that these effects can be reproduced in animal models, where itching sensations per se cannot be reported, but scratching behavior can be observed. (See, for example: Thomas et al., "Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial-scratching", Brain Research, 695: 267-270, 1996; Thomas et al., "Effects of central administration of opioids on facial scratching in monkeys", Brain Res., 585: 315-317, 1992; and Thomas et al., "The medullary dorsal horn: A site of action of opioids in producing facial scratching in monkeys", Anesthesiology, 79: 548-554, 1993).
We have now discovered that certain opiates, which are substantially devoid of central nervous system effects, in topical film-forming formulations possess anti-pruritic activity in addition to antihyperalgesic activity. Accordingly, the present invention also provides safe and effective film-forming compositions for the prevention and treatment of prutitus.